tbuckley/cabot-search huggingface dataset:
Human antigen R regulates autophagic flux by stabilizing autophagy-associated mRNA in calcific aortic valve disease
Authors: Juan Fang, Yi Qian, Jinyong Chen, Dilin Xu, Naifang Cao, Gangjie Zhu, Wangxing Hu, Haochang Hu, Ningjing Qian, Shuangshuang Yang, Jian’an Wang, Xianbao Liu
Journal: Cardiovascular Research (2023)

The incidence of calcific aortic valve disease (CAVD) has risen over the last decade and is expected to continue rising; however, pharmacological approaches have proven ineffective. In this study, we evaluated the role and underlying mechanisms of human antigen R (HuR)-mediated post-transcriptional regulation in CAVD.We found that HuR was significantly upregulated in human calcified aortic valves and primary aortic valvular interstitial cells (VICs) following osteogenic stimulation. Subsequent functional studies revealed that HuR silencing ameliorated calcification both in vitro and in vivo. For the first time, we demonstrated that HuR directly interacted with the transcript of phosphatidylinositol-5-phosphate 4-kinase, type II, alpha (PIP4K2A), which mediates phosphatidylinositol signalling, facilitates autophagy, and acts as an mRNA stabilizer. HuR positively modulated PIP4K2A expression at the post-transcriptional level and consequently influenced the AKT/mTOR/ATG13 pathway to regulate autophagy and CAVD progression.Our study provides new insights into the post-transcriptional regulatory role of HuR in modulating autophagy-positive factors to regulate the pathogenesis of CAVD. Our findings highlight the potential of HuR as an innovative therapeutic target in CAVD treatment.
Turning Down Oxygen to Turn Up Inflammation in CAFs
Authors: Natividad R. Fuentes, Cullen M. Taniguchi
Journal: Cancer Research (2023)

Abstract Pancreatic ductal adenocarcinoma (PDAC) contains a desmoplastic stroma that limits blood perfusion and thus the delivery of nutrients, oxygen, and even therapeutics, creating a hypoxic microenvironment that resists nearly all forms of treatment, including immunomodulating therapy. Cancer-associated fibroblasts (CAF) are the main cellular components and producers of stroma in PDAC. Interestingly, CAFs exist as functionally diverse subpopulations derived from distinct lineages, some of which can be either inflammatory (iCAF) or myofibroblastic (myCAF). While previous work has suggested a link between hypoxia and the iCAF phenotype, direct experimental evidence is lacking. In this issue of Cancer Research, Schwörer and colleagues investigate the role of hypoxia and hypoxia-inducible factor-1α (HIF1α) in maintaining fibroblast heterogeneity and promoting tumor progression in PDAC. The authors use a combination of in vitro and orthotopic techniques to identify a strong role for hypoxia in combination with tumor-derived cytokines in maintaining an iCAF phenotype highlighted by IL6 expression. The authors use an innovative in vitro system to simulate oxygen gradients and use these methods to support their assertions regarding hypoxia as a proinflammatory state. These findings suggest that HIF1α promotes the generation of iCAFs, providing novel insight into CAF heterogeneity. See related article by Schwörer et al., p. 1596
Correction: sFRP2 Supersedes VEGF as an Age-related Driver of Angiogenesis in Melanoma, Affecting Response to Anti-VEGF Therapy in Older Patients
Authors: Mitchell E. Fane, Brett L. Ecker, Amanpreet Kaur, Gloria E. Marino, Gretchen M. Alicea, Stephen M. Douglass, Yash Chhabra, Marie R. Webster, Andrea Marshall, Richard Colling, Olivia Espinosa, Nicholas Coupe, Neera Maroo, Leticia Campo, Mark R. Middleton, Pippa Corrie, Xiaowei Xu, Giorgos C. Karakousis, Ashani T. Weeraratna
Journal: Clinical Cancer Research (2023)

In the original version of this article (1), Supplementary Fig. S4 was incorrect. The CD105 stain used to represent rsFRP2 + alpha-VEGF for Mouse 1 was also used for Mouse 2. The authors provided the correct stain for Mouse 2 and an additional stain for Mouse 3. Supplementary Fig. S4 has been replaced with a corrected version in the latest online HTML version of the article. The authors regret the error.
The pre-mRNA alternative splicing regulated by SRPK2: A new player in alcohol-associated liver disease?
Authors: Zhihong Yang, Wen-Xing Ding
Journal: Hepatology (2023)

1Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46077; USA 2Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA 3Department of Internal Medicine, Division of Gastroenterology, Hepatology & Motility, The University of Kansas Medical Center, Kansas City, KS 66160, USA Financial Support: This study was supported by grants from The National Institute on Alcohol Abuse and Alcoholism R37 AA020518 (W.X.D.) and K01AA26385 (Z.Y.); The National institute on Aging R01 AG072895 (W.X.D.); Indiana Institute for Medical Research (IIMR) and the Central Society for Clinical and Translational Research (CSCTR) Early Career Development Award (Z.Y). Abbreviations: ALD, Alcohol associated liver disease; DEGs, differentially expressed genes; ESRP2, Epithelial splicing regulatory protein 2; FGF21, Fibroblast growth factor 21; mTORC1, Mammalian target of rapamycin (mTOR) complex 1; SREBP1, Sterol regulatory element-binding protein 1; SRPK2, Serine/arginine-rich protein-specific kinase 2; SRSF10, Serine-arginine rich splicing factor 10; SFRS10, Splicing Factor, Arginine/Serine-Rich 10. Correspondence Zhihong Yang, PhD, Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46077; USA. Email: [email protected] Correspondence Wen-Xing Ding, PhD; Department of Pharmacology, Toxicology, and Therapeutics; University of Kansas Medical Center; MS 1018, 3901 Rainbow Blvd., Kansas City, KS 66160. Email: [email protected]
Intratumoral microbiota in HCC: A new kid on the block?
Authors: Junfang Ji, Fubo Ji, Enkhjargal Bayarsaikhan
Journal: Hepatology (2023)

1The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China 2Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang 321000, China 3Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China 4General Laboratory Department, National cancer center of Mongolia, Ulaanbaatar city 210648, Mongolia Financial support: This work was supported by National Key R&D Program of China (2018YFA0800504) (J. Ji), National Natural Science Foundation of China [No.82073055 and 81874054] (J. Ji), the "Pioneer" and "Leading Goose" R&D Program of Zhejiang Province (2023C03052) (J.Ji) Correspondence Junfang Ji, The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang Province, China 310058. Email: [email protected]
Refining the approach to down-staging of HCC prior to liver transplantation: Patient selection, loco-regional treatments, and systemic therapies
Authors: Neil Mehta, R. Katie Kelley, Francis Y. Yao
Journal: Hepatology (2023)

1Division of Gastroenterology, Department of Medicine, University of California, San Francisco 2Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco 3Division of Transplant Surgery, Department of Surgery, University of California, San Francisco Disclosures: Neil Mehta consults for, advises, and received institutional grants from FujiFilm WAKO and Genentech/Roche. He consults for and advises Exact Sciences, Merck, and Exelixis. He received institutional grants from Glycotest and Target Pharmasolutions. Robin K. Kelley consults for, advises, and received institutional grants from Genentech/Roche. She consults for and advises Compass, Exact Sciences, Gilead, Kinnate, and Tyra Therapeutics. She advises and received institutional grants from AstraZeneca, Exelixis, and Merck. She received institutional grants from Aigos, Bayer, BMS, Eli Lily, EMD Serono, Loxo Oncology, Novartis, Partiner Therapeutics, QED, Relay Therapeutics, Surface Oncology, and Taiho. R Katie Kelley and Francis Y. Yao: Indicates co-senior authors Correspondence Neil Mehta, MD, University of California, San Francisco, 513 Parnassus Avenue, Room S-357, San Francisco, CA 94143-0538. Email: [email protected]
Current challenges and future perspectives in treating patients with NAFLD-related cirrhosis
Authors: Maxime Mallet, Cristina Alina Silaghi, Philippe Sultanik, Filomena Conti, Marika Rudler, Vlad Ratziu, Dominique Thabut, Raluca Pais
Journal: Hepatology (2023)

Despite the slow, progressive nature of NAFLD, the number of patients with NAFLD-related cirrhosis has significantly increased. Although the management of patients with cirrhosis is constantly evolving, improving the prognosis of patients with NAFLD-related cirrhosis is a challenge because it is situated at the crossroads between the liver, the metabolic, and the cardiovascular diseases. Therefore, the therapeutic interventions should not only target the liver but also the associated cardiometabolic conditions and should be adapted accordingly. The objective of the current review is to critically discuss the particularities in the management of patients with NAFLD-related cirrhosis. We relied on the recommendations of scientific societies and discussed them in the specific context of NAFLD cirrhosis and the surrounding cardiometabolic milieu. Herein, we covered the following aspects: (1) the weight loss strategies through lifestyle interventions to avoid sarcopenia and improve portal hypertension; (2) the optimal control of metabolic comorbidities in particular type 2 diabetes aimed not only to improve cardiovascular morbidity/mortality but also to lower the incidence of cirrhosis-related complications (we discussed various aspects related to the safety of oral antidiabetic drugs in cirrhosis); (3) the challenges in performing bariatric surgery in patients with cirrhosis related to the portal hypertension and the risk of cirrhosis decompensation; (4) the particularities in the diagnosis and management of the portal hypertension and the difficulties in managing patients awaiting for liver transplantation; and (5) the difficulties in developing drugs and conducting clinical trials in patients with NAFLD-related cirrhosis. Moreover, we discussed the emerging options to overcome these obstacles.
Two important players in poor-prognosis hepatocellular carcinoma: Extrachromosomal circular DNA (eccDNA) and its passenger, the oncogenic miR-17~92 locus
Authors: Ourania Andrisani
Journal: Hepatology (2023)

1Department of Basic Medical Sciences 2Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47906, USA Financial support and sponsorship: 1R21AI170712 (OA) and 5P30CA023168-38S1. List of Abbreviations: BIM, BCL2 like11; CDH1, cadherin 1; Circle-seq, Circle sequencing; DDX5, DEAD-box helicase 5; DSBs, Double Stand Breaks; eccDNA, extrachromosomal circular DNA; ecDNA, circular extrachromosomal DNA; EGFR, Epidermal Growth Factor Receptor; GSK3β, Glycogen Synthase Kinase 3 beta; HCC, Hepatocellular Carcinoma; HSR, homogeneously staining regions; KEGG, Kyoto Encyclopedia of Genes and Genomes; MiR, microRNA; MIR17HG, MiR-17-92 Cluster Host Gene; MYC, proto-oncogene, bHLH transcription factor; NASH, Non-Alcoholic Steatohepatitis; NHEJ, Non-Homologous End-Joining; p21, Cyclin dependent kinase inhibitor 1; PTEN, Phosphatase and Tensin homolog; STAT1, Signal Transducer and Activator of Transcription 1; TCGA, The Cancer Genome Atlas; WGS, Whole Genome Sequencing Correspondence Ourania Andrisani, PhD, Purdue University, 201 S. University Street, West Lafayette, IN 47907-2064. Email: [email protected]
Future directions in acute liver failure
Authors: R. Todd Stravitz, Robert J. Fontana, Constantine Karvellas, Valerie Durkalski, Brendan McGuire, Jody A. Rule, Shannan Tujios, William M. Lee
Journal: Hepatology (2023)

Acute liver failure (ALF) describes a clinical syndrome of rapid hepatocyte injury leading to liver failure manifested by coagulopathy and encephalopathy in the absence of pre-existing cirrhosis. The hallmark diagnostic features are a prolonged prothrombin time (ie, an international normalized ratio of prothrombin time of ≥1.5) and any degree of mental status alteration (HE). As a rare, orphan disease, it seemed an obvious target for a multicenter network. The Acute Liver Failure Study Group (ALFSG) began in 1997 to more thoroughly study and understand the causes, natural history, and management of ALF. Over the course of 22 years, 3364 adult patients were enrolled in the study registry (2614 ALF and 857 acute liver injury—international normalized ratio 2.0 but no encephalopathy—ALI) and &gt;150,000 biosamples collected, including serum, plasma, urine, DNA, and liver tissue. Within the Registry study sites, 4 prospective substudies were conducted and published, 2 interventional ( N -acetylcysteine and ornithine phenylacetate), 1 prognostic [ 13 C-methacetin breath test (MBT)], and 1 mechanistic (rotational thromboelastometry). To review ALFSG’s accomplishments and consider next steps, a 2-day in-person conference was held at UT Southwestern Medical Center, Dallas, TX, entitled “Acute Liver Failure: Science and Practice,” in May 2022. To summarize the important findings in the field, this review highlights the current state of understanding of ALF and, more importantly, asks what further studies are needed to improve our understanding of the pathogenesis, natural history, and management of this unique and dramatic condition.
Advancing Community Living for People with Disabilities
Authors: Ari Ne’eman, David C. Grabowski
Journal: New England Journal of Medicine (2023)

Interview with Ari Ne'eman on opportunities to support access to home- and community-based services for people with disabilities. (14:08)Download Home- and community-based services can address needs of people with disabilities and older adults. U.S. policymakers can accelerate efforts to transition people from nursing homes to the community.
Reviving the NHS—lessons from Labour 1997-2005
Authors: Nigel Crisp
Journal: BMJ (2023)

independent member of the House of Lordsvice chair of the All-Party Parliamentary Group on Global HealthWe have a great deal to learn from the period 1997 to 2005 when, as the King's Fund has reported, the English NHS began the greatest improvement in its history. 1 I was directly involved as a regional director, and from 2000
Retinol Saturase Mediates Retinoid Metabolism to Impair a Ferroptosis Defense System in Cancer Cells
Authors: Guoshu Bi, Jiaqi Liang, Guangyao Shan, Yunyi Bian, Zhencong Chen, Yiwei Huang, Tao Lu, Ming Li, Valeria Besskaya, Mengnan Zhao, Hong Fan, Qun Wang, Boyi Gan, Cheng Zhan
Journal: Cancer Research (2023)

Ferroptosis is an iron-dependent form of regulated cell death induced by the lethal overload of lipid peroxides in cellular membranes. In recent years, modulating ferroptosis has gained attention as a potential therapeutic approach for tumor suppression. In the current study, retinol saturase (RETSAT) was identified as a significant ferroptosis mediator using a publicly accessible CRISPR/Cas9 screening dataset. RETSAT depletion protected tumor cells from lipid peroxidation and subsequent cell death triggered by various ferroptosis inducers. Furthermore, exogenous supplementation with retinoids, including retinol (the substrate of RETSAT) and its derivatives retinal and retinoic acid, also suppressed ferroptosis, whereas the product of RETSAT, 13, 14-dihydroretinol, failed to do so. As effective radical-trapping antioxidant, retinoids protected the lipid membrane from autoxidation and subsequent fragmentation, thus terminating the cascade of ferroptosis. Pseudotargeted lipidomic analysis identified an association between retinoid regulation of ferroptosis and lipid metabolism. Retinoic acid, but not 13, 14-dihydroretinoic acid, interacted with its nuclear receptor and activated transcription of stearoyl-CoA desaturase, which introduces the first double bond into saturated fatty acid and thus catalyzes the generation of monounsaturated fatty acid, a known ferroptosis suppressor. Therefore, RETSAT promotes ferroptosis by transforming retinol to 13, 14-dihydroretinol, thereby turning a strong anti-ferroptosis regulator into a relatively weak one.Retinoids have ferroptosis-protective properties and can be metabolized by RETSAT to promote ferroptosis, suggesting the possibility of targeting retinoid metabolism in cancer as a treatment strategy to trigger ferroptosis.
Alternating 17β-Estradiol and Aromatase Inhibitor Therapies Is Efficacious in Postmenopausal Women with Advanced Endocrine-Resistant ER+ Breast Cancer
Authors: Gary N. Schwartz, Peter A. Kaufman, Karthik V. Giridhar, Jonathan D. Marotti, Mary D. Chamberlin, Bradley A. Arrick, Grace Makari-Judson, Matthew P. Goetz, Shannon M. Soucy, Fred Kolling, Eugene Demidenko, Todd W. Miller
Journal: Clinical Cancer Research (2023)

Strategies to implement estrogen therapy for advanced estrogen receptor-positive (ER+) breast cancer are underdeveloped. Preclinical data suggest that cycling treatment with 17β-estradiol followed by estrogen deprivation can control tumor growth long-term.Postmenopausal women with advanced ER+/HER2- breast cancer with recurrence or progression on ≥ 1 antiestrogen or aromatase inhibitor (AI)-based therapy were eligible. Patients received 17β-estradiol (2 mg orally, three times a day) for 8 weeks followed by AI (physician's choice) for 16 weeks, alternating treatments on an 8-week/16-week schedule until disease progression. Patients then optionally received continuous single-agent treatment until a second instance of disease progression. Endpoints included 24-week clinical benefit and objective response per RECIST, and tumor genetic alterations.Of 19 evaluable patients, clinical benefit rate was 42.1% [95% confidence interval (CI), 23.1%-63.9%] and objective response rate (ORR) was 15.8% (95% CI, 5.7%-37.9%). One patient experienced a grade 3 adverse event related to 17β-estradiol. Among patients who received continuous single-agent treatment until a second instance of disease progression, clinical benefit was observed in 5 of 12 (41.7%) cases. Tumor ER (ESR1) mutations were found by whole-exome profiling in 4 of 7 (57.1%) versus 2 of 9 (22.2%) patients who did versus did not experience clinical benefit from alternating 17β-estradiol/AI therapy. The only two patients to experience objective responses to initial 17β-estradiol had tumor ESR1 mutations.Alternating 17β-estradiol/AI therapy may be a promising treatment for endocrine-refractory ER+ breast cancer, including following progression on CDK4/6 inhibitors or everolimus. Further study is warranted to determine whether the antitumor activity of 17β-estradiol differs according to ESR1 mutation status.
Outpatient Antibiotic Use is Not Associated with an Increased Risk of First-Time Symptomatic Kidney Stones
Authors: Charat Thongprayoon, Lisa E. Vaughan, Erin F. Barreto, Ramila A. Mehta, Kevin Koo, Phillip J. Schulte, John C. Lieske, Andrew D. Rule
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement Antibiotics modify human microbiomes and may contribute to kidney stone risk. In a population-based case-control study using 1247 chart-validated first-time symptomatic kidney stone formers and 4024 age- and sex-matched controls, the risk of kidney stones was transiently higher during the first year after antibiotic use. However, this risk was no longer evident after adjustment for comorbidities and excluding participants with prior urinary symptoms. Findings were consistent across antibiotic classes and the number of antibiotic courses received. This suggests that antibiotics are not important risk factors of kidney stones. Rather, kidney stones when they initially cause urinary symptoms are under-recognized, resulting in antibiotic use before a formal diagnosis of kidney stones ( i.e. , reverse causality). Background Antibiotics modify gastrointestinal and urinary microbiomes, which may contribute to kidney stone formation. This study examined whether an increased risk of a first-time symptomatic kidney stone episode follows antibiotic use. Methods A population-based case-control study surveyed 1247 chart-validated first-time symptomatic kidney stone formers with a documented obstructing or passed stone (cases) in Olmsted County, Minnesota, from 2008 to 2013 and 4024 age- and sex-matched controls. All prescriptions for outpatient oral antibiotic use within 5 years before the onset of symptomatic stone for the cases and their matched controls were identified. Conditional logistic regression estimated the odds ratio (OR) of a first-time symptomatic kidney stone across time after antibiotic use. Analyses were also performed after excluding cases and controls with prior urinary tract infection or hematuria because urinary symptoms resulting in antibiotic prescription could have been warranted because of undiagnosed kidney stones. Results The risk of a symptomatic kidney stone was only increased during the 1-year period after antibiotic use (unadjusted OR, 1.31; P = 0.001), and this risk was attenuated after adjustment for comorbidities (OR, 1.16; P = 0.08). After excluding cases and controls with prior urinary symptoms, there was no increased risk of a symptomatic kidney stone during the 1-year period after antibiotic use (unadjusted OR, 1.04; P = 0.70). Findings were consistent across antibiotic classes and the number of antibiotic courses received. Conclusions The increased risk of a first-time symptomatic kidney stone with antibiotic use seems largely due to both comorbidities and prescription of antibiotics for urinary symptoms. Under-recognition of kidney stones that initially cause urinary symptoms resulting in antibiotic use may explain much of the perceived stone risk with antibiotics ( i.e. , reverse causality).
CD4+ T cell calibration of antigen-presenting cells optimizes antiviral CD8+ T cell immunity
Authors: Elise Gressier, Jonas Schulte-Schrepping, Lev Petrov, Sophia Brumhard, Paula Stubbemann, Anna Hiller, Benedikt Obermayer, Jasper Spitzer, Tomislav Kostevc, Paul G. Whitney, Annabell Bachem, Alexandru Odainic, Carolien van de Sandt, Thi H. O. Nguyen, Thomas Ashhurst, Kayla Wilson, Clare V. L. Oates, Linden. J. Gearing, Tina Meischel, Katharina Hochheiser, Marie Greyer, Michele Clarke, Maike Kreutzenbeck, Sarah S. Gabriel, Wolfgang Kastenmüller, Christian Kurts, Sarah L. Londrigan, Axel Kallies, Katherine Kedzierska, Paul J. Hertzog, Eicke Latz, Yu-Chen E. Chen, Kristen J. Radford, Michael Chopin, Jan Schroeder, Florian Kurth, Thomas Gebhardt, Leif E. Sander, Birgit Sawitzki, Joachim L. Schultze, Susanne V. Schmidt, Sammy Bedoui
Journal: Nature Immunology (2023)

Antiviral CD8+ T cell immunity depends on the integration of various contextual cues, but how antigen-presenting cells (APCs) consolidate these signals for decoding by T cells remains unclear. Here, we describe gradual interferon-α/interferon-β (IFNα/β)-induced transcriptional adaptations that endow APCs with the capacity to rapidly activate the transcriptional regulators p65, IRF1 and FOS after CD4+ T cell-mediated CD40 stimulation. While these responses operate through broadly used signaling components, they induce a unique set of co-stimulatory molecules and soluble mediators that cannot be elicited by IFNα/β or CD40 alone. These responses are critical for the acquisition of antiviral CD8+ T cell effector function, and their activity in APCs from individuals infected with severe acute respiratory syndrome coronavirus 2 correlates with milder disease. These observations uncover a sequential integration process whereby APCs rely on CD4+ T cells to select the innate circuits that guide antiviral CD8+ T cell responses.